DE1620373A1 - Process for the preparation of new heterocyclic compounds - Google Patents

Description

Patent attorneys

SANDOZ AG ^Dr W-Sehdk.Kpl.-lne. P. Wirth Case 600-0057

_gas 2 Dipl.-Ing. G. Dannsnberg

■ Dr. V. Schmied-Kowarzik

Dr. P. Wc-inhold, Dr. D. Gudel 6 Frankfurt / M., Gr. Eschenheimer Str. 39

Process for the preparation of new heterocyclic compounds

The present invention relates to the preparation of compounds of the general formula I in which R, hydrogen, fluorine, chlorine _{or bromine and R 2 are} hydrogen or a lower alkyl group and their acid addition salts.

According to the invention, compounds of the general formula I and their acid addition salts can be obtained by adding compounds of the general formula II in which R 1 and R 1 are as defined above and A is hydrogen or a lower alkyl group. eteh't,

in a known way

Subject to intramolecular ring closure and the compounds of the general formula I thus obtained, optionally subsequently converted into their acid addition salts in a manner known per se.

Compounds of the general formula Ia, which represent a special case of the compounds "of the general formula I (RU = hydrogen)," where R. has the above meaning and "their acid additive salts, can be obtained by using compounds of the general formula Ia Formula III, in which R _{1 has the} above meaning

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and alkyl represents a lower alkyl group on

under reduction

known manner / subject to an intramolecular ring closure and the compounds of the general formula Ia thus obtained optionally then converted into their acid addition salts in a manner known per se.

Compounds of general formula Ib in which R ^{1 has the above meaning and Rp 1 is} a lower alkyl group and their acid addition salts can be obtained by combining compounds of general formula Ia with compounds of general formula IV in which R ₂ 'above Has meaning and Y stands for chlorine, bromine or iodine, is reacted in a manner known per se and the compounds of the general formula Ib thus obtained are optionally subsequently converted into their acid addition salts in a manner known per se.

One embodiment of the process according to the invention consists in that compounds of the general formula II, in which A is a lower alkyl group is in excess of glacial acetic acid or in ß-methoxyethanol in the presence of Na-ß-methoxyethanol heated to boiling on the reflux condenser. Another method consists in using compounds of the general formula II, in which A stands for a lower alkyl group, in a manner known per se, e.g. by heating in an aqueous or aqueous-alcoholic one Solution of an alkali metal hydroxide to the corresponding free acids (compounds of the general formula II, A = hydrogen) saponified and heated it to 140-160 ° for 1-2 hours.

0098U / 1873 · —-

The ring closure of compounds of the general formula III is by reduction, preferably with the aid of nascent hydrogen carried out. A preferred 'embodiment of this method' consists in making connections of the aUg. Formula III in acetic acid dissolves and zinc dust is added to the solution. Instead of acetic acid, however, propionic acid or a solution of hydrogen chloride can also be used be used in dioxane or ethanol. The implementation of compounds of the general formula Ia with Compounds of the general formula IV can be prepared in a manner known per se in an organic organic compound which is inert under the reaction conditions Solvent, e.g. dioxane, dimethylformamide or dimethyl sulfoxide in the presence of a strong anhydrous Base, e.g. potassium tert-butoxide, sodium ethylate or sodium hydride be performed.

The compounds of the general formula I prepared by the above process can then be used in a manner known per se

-4

Manner, e.g. by crystallization from a suitable organic solvents or precipitation of the base as hydro

chloride, which is inert under the reaction conditions, from its solution in an organic solvent

isolated with the help of gaseous hydrogen chloride and

can be cleaned by means of crystallization. The free Bases of the general formula I are then obtained from their salts in a manner known per se, e.g. by alkalizing of the aqueous solutions.

The compounds prepared by the process according to the invention of the general formula I have an asymmetrical one

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Carbon atom and can therefore be obtained both as racemates and in optically active form. The after Racemates obtained according to the invention can be converted into their optically active individual components by methods known per se be split up. Optically active compounds of the general formula I can, however, also be obtained by one this by the method of the present application from their optically active starting resp. Interconnections manufactures. The optically active compounds of the general formula I obtained in this way can, if appropriate, subsequently be used per se known manner can be converted into their acid addition salts.

The compounds of the general formula I used as starting compounds for the preparation of compounds of the general formula I. Formula II are new and their preparation also forms part of the present invention.

The preparation of the compounds of the general formula II can preferably be carried out in such a way that compounds of the general formula VI, in which R. and Rp have the above meanings, are subjected to a reduction in a manner known per se, preferably an electrolytic reduction in acidic solution, for example between lead electrodes and the compounds thus obtained of the general formula V, in which R ^ and R _{2 has the} above meaning, with a lower alkyl chloro or bromoacetate in an organic solvent which is inert under the reaction conditions, for example a lower, aliphatic alcohol (at least 100 ecm solvent per 15 g compound of the general Fo in the oil V) such as methanol _} ethanol or an aromatic

00 981 /, / 187 3 ~

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see hydrocarbon like benzene, in the presence of a tert. Amine, e.g. triethylamine (preferably at least one equivalent should be per equivalent of a compound of the general formula V) a tert. Amine and 1 to 4 equivalents of the alkyl haloacetate are used) while heating at the reflux condenser to boiling.

The compounds of the general formula VI used as starting compounds for the above reaction, the preparation of which also forms part of the present invention, can be obtained, for example, by adding compounds of the general formula VIII, in which R, and Rp have the above meaning, with aqueous alkali, for example a 2 η aqueous sodium hydroxide solution, preferably with heating "up to approx. 100 °, for example on a water bath, (optionally in the presence of solvents which are inert under the reaction conditions and miscible with water, such as tetrahydrofuran, dioxane or lower alcohols) and the resulting compounds of the general formula VII, in which R, and Rp have the above meaning, liberates from the alkali metal salts obtained with the aid of an aqueous acid, for example aqueous hydrochloric acid. The compounds of the general formula VII thus obtained are then in an inert organic solvent under the reaction conditions, be is for example an aliphatic alcohol such as abs. Ethanol (4-40 ecm abs. · Ethanol per 1 g of compound of the general formula VII), dissolved and in the presence of ammonia for 3 ^to 60 hours at 90-150 ° C with a hydrogen pressure of about 150 atm

Use of Raney nickel as a catalyst

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(1-6 g Raney nickel for 12 g compound of the general formula VII) hydrogenated.

Another method for preparing compounds of general formula VI consists in heating compounds of general formula VIII in anhydrous, liquid ammonia and in the presence of sodium in an autoclave to a temperature of 80-160 °. In this reaction, at least 3 ecm of anhydrous, liquid ammonia per 1 g of compound of the general formula VIII should be used. When carrying out the reaction at 100-120 °, it is advantageous to use at least 1 g of sodium for each 45 g of compounds of the general formula VIII. Instead of the sodium used, equivalent proportions of sodium hydride, sodium amide or corresponding derivatives of other alkali metals can be used. At temperatures of 110-120 ° the reaction takes at least 4 hours. The compounds of the general formula IX obtained in this reaction, in which R 1 and R _{2 have the} above meaning, which are likewise in their tautomeric form of the general formula IXa, in which

R, and R _{2 can have the} above meaning, / are then reduced in a manner that is inherently known, e.g. with the aid of sodium borohydride in a suitable solvent, such as a lower aliphatic alcohol (which can contain up to 15% water), such as ethanol, Methanol, propanol or other solvents, respectively. Solvent mixtures, such as methylene chloride / methanol, dioxane / water, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether / water. The reaction is preferably carried out at a temperature of 25-100 ° C for 1 to 10 hours.

0098U / 1873
guided. ,

Compounds of general formula VI can, however, also be obtained by reducing compounds of general formula VIII in a manner known per se, advantageously with the aid of sodium borohydride. This reaction is preferably carried out in 95% ethanol. Instead of ethanol, however, other solvents such as methanol, dioxane, ethylene glycol or diethylene glycol dimethyl ether, each of which can contain up to 15% water, can be used. In addition, other solvents such as benzene, toluene or diethyl ether can be added. The amount of solvent used, respectively. A mixture of solvents should be sufficient to produce a clear solution of a compound of the general formula VIII. The reaction in which at least 1 equivalent (but preferably an excess) of sodium borohydride is added

of the solvent can be carried out at the boiling point / at reflux for 10 minutes (at room temperature for about 17 hours). The compounds of the general formula X obtained in this reduction, in which R _{1 and R 0 have the} above meanings, are then converted in a manner known per se by reaction with chlorinating agents, preferably using thionyl chloride as the solvent and as the chlorinating agent in compounds of the general. Formula XI, in which R _{1 and R 0 have the} above meanings, converted. For this reaction it is advantageous to use a large excess of thionyl chloride. Instead of thionyl chloride alone, thionyl chloride can also be dissolved in one of the

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Reaction conditions inert organic solvents such as benzene or toluene can be used. The reaction with thionyl chloride is advantageously carried out at the boiling point on a reflux condenser. The chlorination of compounds of the general formula X can, however, also be carried out with the aid of phosphorus tri- or pentachloride in an organic solvent which is inert under the reaction conditions, such as chloroform or methylene chloride at 20-60 °. The compounds of general formula XI can then either be converted ^{directly into compounds of general formula VI by heating in anhydrous liquid ammonia to 65 »150 Θ} for 5-25 hours in an autoclave, or by boiling with anhydrous hydrazine to compounds of general formula XII, in which B ₁ and H _{0 have the} above meaning, reacted and these are treated in an acidic solution with an alkali metal nitrite in a known manner, whereby compounds of the general formula VI are likewise formed.

The formula for this preparation of compounds, the "alig" VI compound of the general formula used as starting compound

R. for chlorine and - stand,. Villa wö-rin / R "for mass material /. Is known. The compounds of the general formula VXIIj in which R« stands for a lower alkyl group. _S can be obtained by adding 2-chloro, 2-bromine or 2-fluoro 5 _J , 6-dih2fdro-6 _j! Ll-äioxo-morphanthridine with compounds of the general formula IV in the presence of an acid-binding agent in an organic solvent which is inert under the reaction conditions, for example in a solution of sodium in a

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bath

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lower aliphatic alcohol, such as methanol, 2-bromine or ^ -ΡΙαοΓ - ^, ό-αΙηίταΓΟ-δ, ΙΙ-άίοχο-ηιο ^ ΜΑη ^^ ΰΙη *

. is obtained analogously to the known preparation of the ^ -chlorine compound from Siö-Dihydro-Öill-dioxo-morphanthrldine on Jan well-known way.

The for the production of connections of the alIg. Formula Ia Compounds of the general formula III used as starting compounds are new and also form part of the present invention Invention. ;

Compounds of the general formula III can be obtained, for example, by using o-tolylmagnesium iodide with compounds of the general formula XIII, in which R has the above meaning, in a manner known per se for carrying out Grignard reactions, in an organic solvent inert under the reaction conditions, ζ, B «dry toluene, benzene> tetrahydrofuran, or Uiäthyläther and the resulting compounds of the general formula XIV, where R has the above meaning, in a known manner, for example with the aid of Chromium trioxide in glacial acetic acid with heating on the reflux condenser to boiling su compounds of the general formula XV, in which R _{1 has the} above meaning, oxidized, these then in a manner known per se, for example with N-bromo-succinic acid imide with an organic solvent which is inert under the reaction conditions "cei-i like Ta craciilorkohlerisfcoff with heating ζluh boiling at the Rucki'luasliiüilar, brcmiert and the so-obtained connections of the

O0I814 / Ϊ873

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general formula XVIj in which R., has the above meaning with a lower alkyl ester of aminoacetic acid in. one of the Reaction conditions inert organic solvents such as chloroform or ethanol or a mixture of both, at approx. 0-5 ° and under a nitrogen atmosphere with intermediate formation of compounds of the general. Formula XVII, in which R, and alkyl have the above meaning, to compounds of the general. Formula III implements.

The preparation of optically active compounds of the general formula I and their salts can preferably be carried out in this way be that one of the racemic prepared according to the invention Compounds of the general formula I resp. the racemic basic Output or * intermediate connections of the invention Subjects the process to salt formation with optically active acids, e.g. optically active tartaric acid, in a manner known per se, the resulting diastereoisomeric salt pairs in a manner known per se and separates the optically active components from the salts thus obtained in a manner known per se Way releases. The optically active starting resp. Intermediate connections can then be made as described above Process to the optically active compounds of the general. Formula I are implemented.

The optically active compounds of the general formula I obtained can optionally be added to their Bäureadditio ,,,. Λ-χΙ ^ α s?,:

0 0 9814/1873

The compounds of alIg. Formula I are at Zimiuertemperatur crystallized substances _p with the aid of organic or inorganic acids are converted into their acid addition salts * can * for this purpose are ζ · · Β as organic acids, tartaric acid "alky! Sulfonic acids such as methane. Succinic acid, citric acid ■, acetic acid * maleic acid, fumaric acid, and aromatic acids such as salicylic acid or arylsulfonic acids such as benzenesulfonic acids and as "inorganic .Säuren hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric _s, preferably, the acids. For the production of pharm, usable salse" are used _s you "form water-soluble salts. these include, preferably, the Weinsäure'und" good succinic acid.

Organic acceptable in the present invention compounds of the general _o formula I and their salts ralt ph & rm "manufactured or inorganic acids are valuable Pharraazeutikao They are distinguished by an effect on ö @ s central nervous system .. This manifests itself in a pacifying-as well as an anticonvulsant effect and in the potentiation of the anesthesia caused by barbiturates. The 2-chil "or-5 ^< " flse * i3yl " ^ta 5» 7 s 9d 13b ⁰ tetrahydro-isoindolo [2 _i l = d3 £ l, ⁱ ä-] b, enzoiia2epla ~ 6-on also violates © In © positive effect on the delayed DOPA. (diosyphenylalanine) test, - and potentiates the effect of amphetamine Das. 2.-chlorine-> 5i »7v9

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indolo [2, l-d] [l, 4] benzodiazepin-6-one, on the other hand, is Im delayed DOPA test has no effect and also inhibits the effect of Amphetamine. The compounds prepared according to the invention

and their salts
the general formula I / can be used as sedatives, respectively. as sedatives / hypnotics, as tranquilizers and as an antispasmodic, the S-chloro ^ -methyl- ^ TjO-j ^ b-tetrahydro-isoindolo [2, ld] [l, 4] benzodiazepin-6-one also as an antidepressant .

The daily dose should be 30 to 200 mg for oral or parenteral administration.

The new compounds can be used as medicaments alone or in corresponding medicament forms for oral or parenteral administration For the purpose of producing suitable dosage forms, these are made with inorganic or organic, processed pharmacologically indifferent auxiliaries. as Auxiliaries are used e.g.

for tablets and coated tablets: lactose, starch, talc,

Stearic acid etc. for syrups: cane sugar, invert sugar,

Glucose solutions e.g. for injection preparations: water, alcohols, glycerine,

vegetable oils and the like.

In addition, the preparations can contain suitable preservatives,

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Stabilizers, wetting agents, solubilizers, sweeteners and colorants, flavorings, etc. contain.

Each of the above-mentioned pharmacologically active compounds can be used, for example, for oral administration in the form of a Tablet with the following composition:

1-2 % binding agent (e.g. tragacanth), 3-10 % starch, 2-10 % talc, 0.25-1 # magnesium stearate, corresponding amount of active substance and ad 100 # filler substance, e.g. lactose.

In the following examples, which explain the implementation of the process, the invention in none Way, all temperatures are given in degrees Celsius and are uncorrected *

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Yes

Ib

-CH ₂ -COOA

II

• j α <ι ι ! ,

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-CHg-COEOAlfcyl

III

RJj, Y IV

NHR

VI

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IH

NHR,

O R,

VII VIII

η «νΊ

IX

YOUR,

y y y y "ti

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χι

NO,

'2

τιτ XIII

CH

-OH

NO,

it.

KlV

BATHROOM ΟΓ

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GH.

= O.

XV

CH ₂ Br

¹ C = Ö

XVI

GH,

NH-CH ₂ -COOAIiCyI

C = 0

KO,

XVII

'"■ ΛΙ

; . ■; - 19 -; : ] 6θθ-6θ57

Example 1: 2- chloro-5-methy1-5 <6-dihydrο-6 , 11 -dIoxo morphanthrldine ■ ·

50 g of 2-chloro-5 * 6-dihydro-6 _J ll-dioxo-morphanthridine are dissolved in 500 ecm of anhydrous dimethylformamide and a solution of 5 * 5 g of sodium in 50 ecm of methanol is added to the solution. The reaction mixture obtained in this way is then placed in a vacuum. evaporated to a volume of 125 ecm * After adding 75 g of methyl iodide at 40 °, the whole thing is shaken for several hours then dissolved in a small amount of boiling Äethanols "the ethanol solution is cooled to Ratiratemperatur and the deposited crystals were filtered off" the thus obtained ^ in .Titles said compound melt-in-140 = 142 ° "Naeh frequent Umkristallisierea of mp _o ausAethanolsteigt to 148- 151 °. ■

Example 2s JL-Aniino-1 "(5-p-chloro ° -2- ° methylamlnophen3rl)" - iso-

5y.

22 g of 2-Ghlor-s ^ _i 6 '= - dihydro = 6 _p = ll äioxo> -inorphant ^ RIDIO not included \ w®Taen In 150 cc of liquid viasserfreiem tomoniak dissolved solution thus obtained to OCE is eiae LösiMg "won I ₁ J g Natriraa in 10% anhydrous liquid ammonia was added and the reaction mixture obtained in this way was placed in an autoclave for 16 times a & f use II / 19 (4

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"120 °. It is then cooled to room temperature and the ammonia evaporated. The crystalline residue obtained, consisting of crude l-amino-l- (5-chloro-2-methylaminophenyl) -isoindolin-3-one, is dissolved in chloroform. The chloroform solution is 2 or 3 ^x NIIT water washed and then dried. After evaporation of the chloroform in vacuo, the residue obtained is recrystallized from diethyl ether. the title compound is obtained in the form of white Kris-iaLlen, to decompose at k ^ ^Q kick off.

Example 3s l "(5 ° chloro-2-methylaminophenyl) -isoindolin ~ 3-one

To a solution of the compound obtained in Example 2 after evaporation of ammonia the crude l = amino ~ X- (5 ° chloro-2-methylamiiiophenylH ^so i ⁿ öoliii ~ 3 ~ Qn in 250 cc of 95 $ strength Äethanol 10 g of sodium borohydride was added and the Reaktipnsgeraisch thus obtained during ca _o k hours at reflux heated. "Subsequently, will abgekülilt to room temperature and ..the Uebersehuss of Matriumborhydrid by slow addition of 2"n-hydrochloric> acid decomposes "After the ethanol is evaporated and the ER-

Keep hydroxide solution © residue with 2 ~ n ~ aqueous' matrium / mixed up to a pH of 8 = 9 Ethyl acetate is added to the mixture thus obtained ^ xio produced by the crystallization ιιίτά. The precipitate formed is filtered off until t-Jassrig-3 phase of the filtrate-is in each case 3 3ε with 200 eeia a'athjflacetat esc =

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watered «The organic phases are combined and with a saturated aqueous sodium chloride solution. To Drying, the organic solution is evaporated to 100 ecm. . * "The crystals which have precipitated out are filtered off and then with the crystalline precipitate obtained above agrees »After recrystallization of the crystal mixture from chloroform / ethanol melts the compound named in the title 227-229 °.

Example 4; 2 ~ chlorine ^ ll "hydroxy ^ 5-ra6thyl ~ 3 _j e-dlhydro-6-oxo ~

morphanthridin ^v ;

■ 5-methylr ":

IO g of 2-chloro-5j 6-dihydro76 ^ 11-dioxoHiiorphanthridin are dissolved in 150 ecm 95 ^ SeHi ethanol and the solution is mixed with chloroform until a clear solution is formed *. ^ The clear solution is .- '"""" lait 3.5 g of sodium borohydride over 20 minutes with stirring to 6o ^ö heated; Finally, it is cooled to room temperature and acetic acid is added in small portions until a clear solution is formed. This is evaporated to half its volume and then mixed with 2N aqueous sodium hydroxide solution until a slightly alkaline reaction is achieved. The decomposition product precipitated after the addition of water is filtered off, washed with water and dried * The compound named in the title thus obtained melts at 195-198 *. i

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Example 5; 2, 11-DIch1 or-5-methyl - 5 , 6 - d i hy el ro -6 - oxomorphanthrldln

8.5 g of 2-chloro-II-hydroxy-5-methylr5,6-dihydro-6-oxo-mo: q3hanthridine are dissolved in 120 ecm thionyl chloride and the so The solution obtained was heated on the reflux condenser for 3 hours. By adding 60 ecm of benzene and subsequent evaporation to dryness and dissolution of the precipitate obtained in a further 60 ecm of benzene, and repeated evaporation to dryness the excess of thionyl chloride is removed. After recrystallization of the residue from methylene chloride, the Compound named in the title with a melting point of 188-190 °.

Example 6: I - (^ - chloro - ^ - methylaminophenyl) -isolndolin-3-one

5 g of 2, ll-dichloro-5-methyl-5,6-dihydro-6-oxo-morphanthridine become dissolved in 100 ecm of dry liquid ammonia and the resulting solution heated to 100 ° in an autoclave for 16 hours. The ammonia is then evaporated from the reaction mixture and the residue in 100 ecm of hot chloroform, which is slightly Contains ethanol, dissolved. The solution obtained is washed with water, then dried over sodium sulfate and finally evaporated to 100 ecm. The unusual one compound named in the title is filtered off and extracted from chloroform / methanol recrystallized. Sap. 225-227 °.

example f: 2-amino-l- (5-chloro-2-methylaminophenyl) -iso-

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"^;;; - ■■", ■. ^Λ ν

A mixture consisting of 5.8 g of 2, ll-dichloro-5-m 6-oxo-morphanthrIdin and 60 ecm anhydrous hydrazine, is used during Ϊ hour on the reflux condenser .heated and then in ' Waeser registered. This is followed by

Extract methylene chloride and oil methylene chloride solution first with water and then with saturated *. Aqueous sodium chloride solution washed = after drying over sodium sulfate it is evaporated to dryness in vacuo! The oil obtained as residue is recrystallized from diethyl ether. After further recrystallization from methylene chloride / diethyl ether, the compound mentioned in the title melts (with 1 mol of diethyl ether ) at 62 ~ 64 ⁰ _O

Example '81 1- (^ -Chior «2 ~ methylamineQpheny1) ° -isoindoline ° 3- ° o ^

0 ^ 36 g 2 = Mino = 1 = C5-chloro-2-methylaminophenyl) -isoindolini = 3-oß are suspended in 3 _# 5 ecm 1N aqueous hydrochloric acid and the suspension thus obtained is cooled in an ice bath. A solution of 0.9 g of sodium nityite in 2 cm of mass is then added to the cooled suspension with stirring and further cooling. Ο The precipitate formed is filtered off and washed with mass. After! ^ Crystallization, the compound mentioned in the title melts at 225-227®V - ·. _: \. . ' : - ^:

Example 9'ί 5 ^% -chlorine-g ⁸ -methylaminobenz op henon -g-carboxylic acid

20 g of 2-chloro-5-methyl "5 _i , .6-aihydro = 6 _J , ll-dioxo-morphantliridia, 175 ecm of 2N aqueous sodium hydroxide solution" are mixed and the mixture thus obtained is heated for 50 minutes in a steam bath ^"-:;" '.; 00981-4 / 1,873th. :

BATH ORIGINAL

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The clear solution obtained is cooled to room temperature, the sodium salt of the compound mentioned in the title precipitating out. This is mixed with 150 ecm of water and then with 150 ecm of 2N aqueous hydrochloric acid with stirring. The crystals obtained in this way are filtered off and washed with water. After drying the washed crystals and recrystallization from chloroform / methanol, the title compound melts at 226-230 ^0th

) ' Example 10: 1- (5-chloro-2-methylaminophenyl) -isoindolin-3-one 12 g of 5'-chloro-2 ^! -methylaminobenzophenone-2-carboxylic acid with 70 ecm abs. Ethanol mixed and the resulting mixture saturated with ammonia while cooling. After adding 3 g of Raney nickel, the mixture is for several hours at

Atm. 110-130 ° and a hydrogen pressure of 150 / hydrogenated .. After

Filtering off, the filtrate is cooled to room temperature and the solvent is evaporated. The residue is made from chloroform recrystallized. The so obtained Ver-1

bond melts at 225-227 °.

Example 11; 1- (5-chloro-2-methylaroinophenyl) isoindoline

20 g of l- (5-chloro-2-methylaminophenyl) -isoindolin-3-one are dissolved in 200 ecm of a 1: 1 mixture of water and conc. Dissolved sulfuric acid. The solution obtained is cooled to room temperature and then treated with 200 ecm of water. This diluted solution is filled into a beaker fitted with a lead electrode (200 cm ² surface).

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A porous vessel (diaphragm) is then filled / Sulfuric acid of the same concentration and provided with • a lead electrode of the same surface as the thinned Solution dipped and the first "electrode with the negative and the second electrode with the positive pole of a 12-volt battery tied together. The solution in the cathode chamber

between is carried out with intensive stirring for 15 hours at a temp. / Electrolyzed at 10 and 25 °. Then the porous Vessel removed and the sulfuric acid in the beaker while cooling with 50 # aqueous sodium hydroxide solution neutralized. The crystals which have precipitated out are filtered off. The compound named in the title thus obtained melts at 133-135 °.

Example 12; Ethyl 1- (5-chloro-2-methylaminophenyl) isoindoline-2-acetic acid

15 g of l- (5-chloro-2-methylaminophenyl) -isoindoline are dissolved in 14 g of brcraacetic acid-e-ethyester and a solution of 11 ecm of triethylarain and 250 ecm of abs. Dissolved ethanol and the resulting solution heated on the reflux condenser for 2 hours. It is then evaporated to dryness and the residue is dissolved in benzene. The benzene solution obtained is washed with water, dried and evaporated to dryness, whereby the compound named in the title remains. After crystallization from diethyl ether, the compound mentioned in the title melts at 79-81 °. Example 15: 2-chloro-5-methyl »5i7> 9 * 13b - tetrahydro-isoindolo

Ö0S8U / 1873 bad original

The ethyl l- (5-chloro-2-methylamlnophenyl) isoindoline-2-acetic acid obtained according to Example 12 is dissolved in 150 ecm of glacial acetic acid and the resulting solution is heated to boiling, with about half the amount of acid is slowly distilled off, then it is evaporated to dryness in vacuo. The residue is dissolved in methylene chloride and hydrogen chloride gas is passed into the solution thus obtained. After adding diethyl ether falls the hydrochloride of the compound named in the title

from m.p. 263-266 ° C. After being released from their salt according to known Methods (dissolving in aqueous sodium hydroxide solution, extracting with methylene chloride and evaporating the solvent) melts the free base at 171-173 ° C.

The analogously represented S-methyl ^^^ l ^ b-tetrahydro-isoindolo- [2, l-d] [l, 4] benzodiazepin-6-one hydrochloride melts at 255-257 °.

Example 14; Enantiomers of l- (5-chloro-2-methylamino-phenyl) -

isoindolln

To a solution of 10.3 g of rac. 1- (5 ~ chloro-2-methylaminophenyl) -isoindoline in 120 ecm of ethanol and 6o ecm of methylene chloride is added to a solution of 6 g of D-tartaric acid in 75 ecm of ethanol. The mixture obtained is concentrated, the tartrate of the (+) - base crystallizing out, while the tartrate of the (-) - base remains in solution. The deposited precipitate is filtered off and the base is released from its salt by partitioning the precipitate between methylene chloride and dilute aqueous sodium hydroxide solution. The methylene chloride solution is dried and then freed from solvents in vacuo. After recrystallization from methylene chloride / methanol, (+) - 1- (5-chloro-2-methylarainophenyl) -isoindoline with a melting point of 100-102 ° C. BAD is obtained

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β + 44 ° (c = 1.5 in chloroform). The filtrate, which contains the tartrate of the (-) - base, is evaporated to dryness in vacuo and the residue is partitioned between methylene chloride and dilute aqueous sodium hydroxide solution. The organic phase is then dried and then the solvent is evaporated in vacuo. The residue obtained in this way, which mainly consists of the (-) - base, is converted into the crystalline L - (-) - tartrate in the manner described above by adding L-tartaric acid. After dissolving from its salt as described above, the (-) - 1- (5-chloro-2-methylaminophenyl) -isoindoline melts at 100-101 °. Ea] ^ J ₆ = -43.6 ° (c = 1.5 in chloroform).

Example 15: Enantiomers of l- (5-chloro-2-methylaminophenyl) -isoindoline-2-acetic acid ethyl ester

3 6 (+) - 3 .- (5-chloro-2-methylaminophenyl) -isoindoline, 2 g bromo ester
acetic acid-ethyl / and 2 g of triethylamine are in 75% ethanol during? Heated for 2 hours on the reflux condenser. It is then evaporated to dryness and the residue obtained is dissolved in benzene. The benzene solution is gradually washed in each case with water, 2N aqueous sodium hydroxide solution, 1N hydrochloric acid and saturated aqueous sodium chloride solution. It is then evaporated to dryness, the (+) - 1- (5-chloro-2-methylaminophenyl) -isoindoline-2-acetic acid ethyl ester being obtained as a residue.

0098U / 1873

BAD ORSQIMM.

- 28 - 6οο-βθ57

By replacing the o.e. (+) - 1- (5-Chloro-2-methylaminophenyl) -isoindoline by (-) - 1- (5-chloro-2-methylaminophenyl) -isoindoline obtained by the process described above the (-) - l- (5-chloro-2-methylaminophenyl) -isoindoline-2-Esslgsäureäthyl- ester.

Example 16: (-) - 2-chloro-5-methyl-5,7 ₁ 9,15b-tetrahydro-isoindolo- [2, l-d3 [l, 4] benzodia7. epin-6-on

The (+) - 1- (5-chloro-2-methylaminophenyl) -isoindoline-2-acetic acid ethyl ester obtained by the method of Example I5 is dissolved in 30 ecm of glacial acetic acid and the resulting solution during Heated to boiling for 2 hours, some of the acetic acid distilling off, then all of the acetic acid is through

in a vacuum

Evap / remove, and the residue obtained in methylene chloride solved. After washing the methylene chloride solution with in each case a dilute aqueous sodium hydroxide solution and the solution is evaporated to dryness with water and the residue is recrystallized from diethyl ether .. After filtering off and Drying melts the compound named in the title at 173-175 °.

^{[a] =} " ²⁰⁷ ° ( ^{c =} ° ' ^{5 in Aethano1} ) ·

Example 17; (+) - 2-Chloro-5-methyl-5,7,9 * 13b-tetrahydro-iso indolo [2,1-d] [1,4] benzodiazepin-6-one .

The (-) - l- (5-chloro-

2-methylaminophenyl) -isoindoline-2-acetic acid ethyl ester is dissolved in 30 ecm of glacial acetic acid and the resulting solution for 2 hours

00S8U / 1873

6θΟ-βθ57

Τ620373

heated on the reflux condenser, some acetic acid distilling off

in a vacuum

The remaining acetic acid / is then distilled off

and the residue obtained is dissolved in methylene chloride. After washing the methylene chloride solution with one diluted each aqueous sodium hydroxide solution and with water the solution is evaporated to dryness. After recrystallizing the Residue from diethyl ether and filter off and drying

20 you get the compound named in the title. Ca] ₁ - ^ g = + 210 °

(c = 0.5 in ethanol).

Example 18: 5-chloro-2 ^f -methyl-2-nitro-benzhydrol

To a solution of 5-chloro-2-nitro-benzaldehyde in 200 cc of dry toluene is added a solution of 26 g o-Tolylraagnesium iodide in 300 cc of diethyl ether at -65 ^0th The mixture is then stirred at this temperature for 3 hours, then warmed to -10 ° and slowly 20 ecm of a saturated aqueous solution of ammonium chloride is added. The aqueous phase is acidified with dilute hydrochloric acid and the org. Phase deposited. The aqueous phase is then extracted 2 χ with benzene. The organic phases are combined, washed out with water and then dried over sodium sulfate. After the organic solvents have been evaporated off in vacuo, the residue is recrystallized from diethyl ester. The 5-chloro-2 ^f -methyl-2 * -aitro-benzhydrol thus obtained melts at 130-132 °.

ÖftÜ8U / -i873

BATH

- 30 - 600-6057

Example 19: ^ -Chlor-2'-methyl-2-ntro-benzophenone

A suspension of 6.5 g of chromium trioxide in 40 ecm of glacial acetic acid is added over 30 minutes to a solution of 9.5 g of 5-chloro-2 ^{l -raethyl-2-nitro-benzhydrol in 40 ecm of glacial acetic acid, boiling on a reflux condenser.} Thereafter, the boiling is continued for 15 minutes * After cooling, the reaction mixture thus obtained are added to 500 cc of water, the precipitated 5-chloro-2'-methyl-2-nitro-benzophenone in yellow prisms, mp. II5-II6 ^0th

- Example 20; 5-chloro-2 '- "brcfluoriethyl-2-nitro-benzophenone

A mixture consisting of 3.6 g of 5-chloro-2'-methyl-2-nitrobenzophenone, 2.5 g of N-bromosuccinimide and 0.1 g of dibenzoyl peroxide In 35 ecm carbon tetrachloride is added for 3 hours

. heated on the reflux condenser. Then the mixture is with Diluted methylene chloride, washed 2 χ with water, over

. Sodium sulfate dried and finally the organic solvents evaporated in vacuo. The residue obtained is recrystallized from methylene chloride / diethyl ether. ^{The 5-chloro-2 l} -bromomethyl-2-nitro-benzophenone obtained in the form of yellow prisms melts at 137-139 °.

' Example 2Ir - 1-C5-chloro-2-πltrcι- »phenyll ^ -isόlndolo-g-Esslgsgure ^

ethyleater
1 # 8 g of 5-chloro-2 ^I -bromo "ethyl-2-nitro-benzophenone \ ind 1 g Glycln acid ethyl ester are dissolved in a mixture of 40 cc of chloroform and 500 cc of ethanol and the resulting solution

^BATH

- 31 - 600-6057

162Ö373

for 48 hours at a temperature between 0 and 5 ° in Stirred in a nitrogen atmosphere. Then the solvents evaporated in vacuo and the crude product obtained as residue is used further without purification.

Example 22; 2-chloro-5.7 _J 9,13b-tetrahydrQ-isoindolo [2, l-d] [1,43-benzo; iiazepin-6-one

The crude product obtained according to Example 21 is 100 ecm Dissolved acetic acid, added 4 g of zinc dust to the solution and the resulting mixture for 3 hours at room temperature (20 °) stirred. The unreacted zinc is then filtered off and the filtrate is evaporated in vacuo. The residue is dissolved in chloroform and the solution in each case with 2N aqueous Sodium carbonate solution and washed with water. After drying over Sodium sulfate, the organic phase is evaporated to approx. 10 ecm, wherein the 2-chloro-5,7,9,13b-tetrahydro-isoindolo-. [2,1-d] [1,4] benzodiazepin-6-one with a melting point of 258-200 ° crystallized out.

Example 23: 2-Chloro-5-methyl-5,7 ^ 9> 13b-tetrahydro-iBoindolo- '"- - [2,1-d3 [1,4 3-benzodiazepin-6-one

6 g 2-0110 ^ 5,7,9> 13b-tetrahydro-isoindoloL2, l-d] Ll, 4] benzodiazepin-6-one are in 200 ecm abs. Dissolved dimethylformamide and added 1.3 g of a 56 l suspension to the resulting solution at 60 ° of sodium hydride added in mineral oil. The reaction mixture

OOilU / 1873

- 32 - 600-6057

is heated to 70 ° and admixed with 4.3 g of methyl iodide for a further 30 minutes. Mixture is then stirred for a further 1 hour at 50-60 ⁰ and then added water. After the reaction mixture has evaporated to dryness, the residue obtained is dissolved in 300 ecm of methylene chloride and the solution obtained is washed with water. After the solution has been dried over sodium sulfate, the solvent is evaporated off in vacuo and the residue is dissolved in diethyl ether / methylene chloride. The solution is filtered and then saturated with dry hydrogen chloride gas.

The 2-chloro-5-methyl-5,7,9,13b-tetrahydroisoindolo [2, l-d] [l, 4] benzodiazepin-6-one which precipitated in the process hydrochloride melts at 263-268 °.

The therefrom by known methods (dissolving in aqueous sodium hydroxide solution, extracting with diethyl ether / methylene chloride and evaporation of the solvents) liberated base melts at I65-I72 ^0th

The 2-chloro-5-ethyl-5,7,9,13b-tetrahydroisoindolo [2, ld] [l, 4] benzodiazepin-6-one hydrochloride, which can be prepared analogously, melts at 283-284 °. The free base melts at I68-I70 ⁰ C.

009814/1873

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example 2k:

Description of a tablet composition: '

2-chloro-5-methyl ~ 5j, 7 , 9, 13b ~ tetrahydro-isoindolo-

[2,1-d} [1,4] benzodiazepin-6-one ................... 50 g

Lactose 39.5 g

Corn starch powder ................................. 5g

Talc 3 g

Magnesia stearate ................................. 0.5 p

Alcohol SD-30)

in necessary quantities
Best. Water

The weight of the tablet produced depends on the too
administered dose of active ingredient.

0008 14 / ti? 3 BAD ORIGINAL

Claims (27)

1. Compounds of the formula I in which R is hydrogen, fluorine, chlorine or bromine and R ~ are hydrogen or a lower alkyl group, and their acid addition salts and optical antipodes. 2. 2-Chloro-5-methy1-5,7,9,13b-tetrahydro-isoindolo [2,1-d3 ti, 4] -benzodiazepin-6-one. 3. 5-Methyl-5 * 7 * 9,13b-tetrahydro-isoindolo [2, l-d] [1,4] benzodiazepin-6-one. 4. (-) - 2-Chloro-5-methyl-5,7 # 9,13b-tetrahydro-isoindolo [2, l-d] [1,4] benzodiazepin-6-one. 5. (+) - 2-chloro-5-methyl-5,7,9,13b-tetra "hydro-isoindolo [2, l-d] [1,4] benzodiazepin-6-one. 6. 2-Chloro-5,7,9 # 13b-tetrahydro-isoindolo [2, l-d] [1,43-benzodiazepJLn-6-one. 7. 2-Chfor-5 ~ methyl-5,7 # 9 »13b-tetrahydro-isoindolo [2, l-dJE1, 4I-benzodiazepin-6-one. 8. 2-Chloro-5-ethyl-5 »7, 9, 13b-tetrahydro-isoindolo [2,1-ä 1E4,1] -benzodiazepin-6-one. 9. Pharmaceutical preparation, characterized by a content to hostilities of the formula I as an active ingredient. ~ "* ~ ~ ■ ..-- 003814/1873 Nice documents (Art. 7 § I Fig. 2! Jr. 1 sentence 3 de * Xndwinfl «^. V. - 35 - 500-6057 1 10. Process for making compounds of the form wherein R, hydrogen, fluorine, chlorine or bromine and R is hydrogen or mean a lower alkyl group and their acid addition salts, characterized in that one either a) Compounds of the formula II in which R ₁ and R_ have the above meaning and A stands for hydrogen or a lower alkyl group, subjects to an intramolecular ring closure or b) for the preparation of compounds of the formula Ia, in which R has the above meaning, compounds of the formula III, wherein R, has the above meaning and alkyl stands for a lower alkyl group, with reduction to an intramolecular one Subject to ring closure or c) for the production of compounds of alIg. Formula Ib, in which R _{1 has the} above meaning and R _p 'stands for a lower alkyl group, compounds of the formula Ia, in which R ^ has the above meaning, with compounds of the formula _t IV, in which R _{2 has the} above meaning and Y is chlorine, bromine or iodine, converts, and the compounds of the formula I thus obtained are optionally converted into their acid addition salts and / or their optical ones Antipodes separates. 11. The method according to claim 10, characterized in that the ring closure of compounds of the formula TI, wherein A is a lower alkyl group is in an over- 0098U / 1873 BATH ORIGINAL Shot of glacial acetic acid or in ß-methoxyethanol in the presence of wet methoxyethanol is carried out. 12. The method according to claim 10, characterized in that the ring closure of compounds of the formula II in which A is hydrogen is carried out by heating to a temperature of 140-160 ° C for 1-2 hours. 13. The method according to claim 10, characterized in that the Ring closure of compounds of the formula III according to the process variant b) is carried out by reduction with the aid of nascent hydrogen. 14. The method according to claim 10, characterized in that the Reaction of compounds of the formula Ia with compounds of the formula IV according to process variant c) in an inert organic Solvent and in the presence of a strong anhydrous base is carried out. 15. Compounds of the formula II in which R is hydrogen, fluorine, chlorine or bromine and R "denotes hydrogen or a lower alkyl group and A represents a lower alkyl group, and their acid addition salts. 16. Ethyl 1- (5-chloro-2-methylaminophenyl) isoindoline-2-acetic acid. 0 098 H / 1873 - 37 - 600-6057 17. (+) -l- (5-chloro-2-methylaininophenyl) -lsoindoline-2-acetic acid ethyl ester. 18. (-) - 1- (5-Chloro-2-methy1aminopheny1) -isoindoline-2-acetic acid ethyl ester. --- 19 · Process for the preparation of compounds of the formula XI, in which R. is hydrogen, “fluorine”, chlorine or bromine and R _{p is} hydrogen or a lower alkyl group and A stands for a lower alkyl group, characterized in that compounds are | gen of the formula V in which R. and R ₂ have the above significance, with a lower chlorine or Bromessigsäurealkylester. 20. Compounds of the formula IH in which R _{1 is} hydrogen, fluorine, chlorine or bromine and alkyl is a lower alkyl group. 21. l- (5 ^ chloro-2-nitro-phenyl) -isoindolo-2-acetic acid ethyl ester. ( 22 Process for the preparation of compounds of the formula III, where R. is hydrogen, fluorine, chlorine or bromine and alkyl means a lower alkyl group, characterized in that ■ to compounds of the formula XVI, in which R. has the above meaning, ■ it converts a lower alkyl ester of aeinoesslgsäure. 23. Compounds of the formula V in which R _{1 is} hydrogen, fluorine, chlorine or Bro «and R _{2 is} hydrogen or a lower alkyl group. 009814/1873 ..., "" ^ _n original - 38 - bCC-6057 24. 1- (5-chloro-2-methylaminopheny1) -isoindoline. 25. A process for the preparation of compounds of the formula V in which R, hydrogen, fluorine, chlorine or bromine and R is hydrogen or a lower alkyl group, characterized in that compounds of the formula VI in which R ₁ and R are as defined above are reduced . 26. Compounds of the formula VI in which R _{1 is} hydrogen, fluorine, chlorine or bromine and R is hydrogen or a lower alkyl group. 27. 1- (5-Chloro-2-methylaminophenyl) -isoindolin-3-one. 28 ·. Process for the preparation of compounds of the formula VI in which R _{1 is} hydrogen, fluorine, chlorine or bromine and R _{2 is} hydrogen or a lower alkyl group, characterized in that nan either a) Compounds of the formula VII in which R ₁ and R _{2 have the} above meanings , hydrogenated in the presence of ammonia, or b) Compounds of the formula IX or IXa, in which R ₁ and R _{2 have the} above meanings, reduced, or e) Compounds of the formula XI, in which R. and R _{2 have the} above meanings, treats salt Aaeoniak, or d) Compounds of the formula XII, in which R ₁ and R _{2 have the} above meanings, treated in acidic solution as an alkali metal nitrite. 3700 / -1 / Il 0098U / 1873